Is TRPM4 p.Gln8= (c.24G>A) pathogenic?

TRPM4 p.Gln8= (c.24G>A) is classified Uncertain significance in TRPM4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-18). Very rare (popmax 0.000174%, nfe); Associated with erythrokeratodermia variabilis et progressiva 6.

What condition is associated with TRPM4 p.Gln8= (c.24G>A)?

TRPM4 p.Gln8= (c.24G>A) is associated with erythrokeratodermia variabilis et progressiva 6, progressive familial heart block type IB (ClinVar).

How common is TRPM4 p.Gln8= (c.24G>A) in the general population?

TRPM4 p.Gln8= (c.24G>A) is very rare (popmax 0.000174%, nfe) (gnomAD).

How is Erythrokeratodermia variabilis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TRPM4 p.Gln8=

c.24G>A · rs2041543043 · VCV1503929

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Conditions

erythrokeratodermia variabilis et progressiva 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Pangolin	Δ0.48	loss · gain 0.02 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 9.4	phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,146,468 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00013% 2/1,535,094 alleles · very rare exomes 1/1,382,920 · genomes 1/152,174 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TRPM4
Protein: p.Gln8=
Coding: c.24G>A
MANE Select: NM_017636
dbSNP: rs2041543043
Type: single nucleotide variant
Location: chr19:49157890 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.51 · 42 PDB
Residue 8: an α-helix

Full TRPM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

erythrokeratodermia variabilis et progressiva 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial heart block type IB

For Erythrokeratodermia variabilis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TRPM4 p.Gln8Leu Uncertain significance ★★ ⚠ same residue
TRPM4 p.Ile1040Thr Pathogenic/Likely pathogenic ★★ same condition
TRPM4 p.Ile376Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRPM4 c.1050+1G>A Uncertain significance ★★ same condition
TRPM4 c.1150+5A>T Uncertain significance ★★ same condition
TRPM4 c.1150+6A>G Uncertain significance ★★ same condition
TRPM4 c.1263+1G>A Uncertain significance ★★ same condition
TRPM4 c.1263+2T>G Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/trpm4-p-gln8 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown